Throughout this application, various publications are referenced to in full citations. The disclosures of these publications are hereby incorporated by reference into this application to describe more fully the state of the art to which this invention pertains.
Melanin-concentrating hormone (MCH) is a cyclic 19-amino acid peptide produced by neurons in the lateral hypothalamus and zona incerta of the brain. Mammalian MCH is conserved between rat, mouse, and human, exhibiting 100% amino acid homology, and the effects of MCH are mediated through receptors that belong in the rhodopsin superfamily of G protein-coupled receptors. Presently, two receptor subtypes for MCH have been identified in humans, MCH1 and MCH2.
The link between MCH1 and the effects of MCH on feeding was suggested by reports on the phenotype of the MCH1 knockout mice. Independent groups generated knock-out mice with the targeted deletion of the MCH1 receptor. The phenotype of these mice was lean, hyperphagic and hypermetabolic, with increased resistance to diet-induced obesity (D. J. Marsh, et al., Proc. Natl. Acad. Sci. 2002, 99, 3240-3245). These observations evidence that MCH1 antagonists are useful to treat obesity.
To further assess the physiological role of the MCH1 receptor, SNAP-7941, a selective MCH1 small molecule antagonist, was evaluated in several animal models (B. Borowsky, et al., Nature Medicine, 2002, 8, 825-830). Pharmacological blockade of the MCH1 receptor with SNAP-7941 produced a profile similar to clinically used anti-depressants and anxiolytics in behavioral models of depression and/or anxiety: the rat forced-swim, rat social interaction and guinea pig maternal-separation vocalization tests. These observations evidence that MCH1 antagonists are useful to treat depression and anxiety.
Current treatments for depression, anxiety and obesity are on the market. However, numerous patients do not respond to current treatments. Hence, there remains the need for alternative methods of treatment.